Question 12 of 13: Seven Multi-Step Syntheses from Benzene

Question 12: Seven Multi-Step Syntheses from Benzene

Question text not reproduced: the examination questions are © Engineers and Geoscientists BC. Open the official past paper (linked at the top of this page) to read the question, then follow the worked solution below.

(a) 4-Bromoaniline

Order matters: brominate before nitrating, because Br (an o,p-director) must be in place to direct the nitro group para to itself.

1. Benzene + Br₂/FeBr₃ → bromobenzene.
2. HNO₃/H₂SO₄, directed para to Br (major, sterically preferred) → 1-bromo-4-nitrobenzene.
3. Reduce the nitro group (Fe/HCl, or H₂/Pd, or SnCl₂/HCl) → 4-bromoaniline.

(b) 2-Bromo-4-nitrotoluene

Install the o,p-director (methyl) first via Friedel–Crafts alkylation (methyl cation cannot rearrange), then let it direct both later steps — both the nitro (para, major) and the bromo (the remaining open ortho position) end up exactly where methyl's own directing preference already sends them, so the two substitutions simply fill methyl's two most-favoured open positions in turn.

1. Benzene + CH₃Cl/AlCl₃ → toluene.
2. HNO₃/H₂SO₄, para to CH₃ (major) → 4-nitrotoluene.
3. Br₂/FeBr₃: with para blocked by NO₂, bromination goes to the remaining position ortho to CH₃ (also meta to NO₂ — both directors reinforce the same site) → 2-bromo-4-nitrotoluene.

(c) 1-(2-Isopropyl-5-nitrophenyl)ethan-1-one

Install the alkyl group first (o,p-director), acylate ortho to it, then nitrate: the acetyl group's own meta-preference and the isopropyl group's own para-preference point at the same ring position, so the final nitration is unambiguous.

1. Benzene + (CH₃)₂CHCl/AlCl₃ (stable secondary cation, no rearrangement) → cumene.
2. CH₃COCl/AlCl₃, directed ortho/para by the isopropyl group → 2-isopropylacetophenone. The bulky isopropyl group makes the para ketone the major product, so the ortho isomer has to be separated from it (chromatography/distillation); this is the yield-limiting step of the route, but no ordering of the three substitutions avoids it, because the acetyl must be ortho to the alkyl group and Friedel–Crafts reactions fail on a nitrated ring.
3. HNO₃/H₂SO₄: the position meta to the (deactivating, meta-directing) acetyl group is also para to the isopropyl group — both substituents reinforce the same site → the target nitro compound.

(d) 4-Aminobenzoic acid (PABA)

The oxidation state of the eventual carboxyl group must be installed last: as a methyl group, CH₃ is an o,p-director (needed to place NO₂ correctly); oxidised early to –COOH, it would become a meta-director and misdirect the nitration.

1. Benzene + CH₃Cl/AlCl₃ → toluene.
2. HNO₃/H₂SO₄, para to CH₃ (major) → 4-nitrotoluene.
3. KMnO₄, heat (benzylic oxidation of the methyl to –COOH; unaffected by the ring nitro group) → 4-nitrobenzoic acid.
4. Reduce NO₂→NH₂ (Fe/HCl or H₂/Pd) → PABA.

(e) Sodium 4-propylbenzenesulfonate

A primary 3-carbon chain must be installed via acylation + reduction, never by direct Friedel–Crafts alkylation with 1-chloropropane (which would rearrange to the secondary, isopropyl cation).

1. Benzene + CH₃CH₂COCl/AlCl₃ → propiophenone.
2. Clemmensen reduction (Zn(Hg)/HCl) → propylbenzene.
3. Fuming H₂SO₄/SO₃, para to propyl (major) → 4-propylbenzenesulfonic acid.
4. NaOH (neutralise) → sodium 4-propylbenzenesulfonate.

(f) 4-Bromo-2-propylaniline

The bromine must land meta to the propyl group — a position a simple alkyl (o,p-director) can never deliver on its own. The fix is to install the eventual amine first (ortho to propyl, exactly where propyl's own directing preference already sends nitration), then let the far stronger amine director control the last step: bromination para to –NH₂ lands, purely as a consequence of the ring geometry, at the position that is meta to propyl.

1. Benzene + CH₃CH₂COCl/AlCl₃, then Clemmensen reduction → propylbenzene (same two steps as in part (e)).
2. HNO₃/H₂SO₄: propyl directs ortho/para; isolate the minor ortho product (the para isomer is major and must be separated away) → 2-nitropropylbenzene.
3. Reduce NO₂→NH₂ (H₂/Pd or Fe/HCl) → 2-propylaniline.
4. Acetylate the amine first (Ac₂O) to moderate its powerful activating effect and avoid polybromination, then Br₂: bromination goes para to the acetamido group (the remaining ortho position is blocked by the propyl group) → the 4-bromo acetanilide.
5. Hydrolyse the acetamide (H₃O⁺, heat, or NaOH/H₂O) → 4-bromo-2-propylaniline.

(g) 2-Chloro-1-ethenyl-4-propylbenzene (2-chloro-4-propylstyrene)

Two things fix the plan. (1) The chlorine must end up meta to the propyl group, which an alkyl group can never deliver, so Cl is introduced while the side chain is still a meta-directing ketone (propiophenone), and only then reduced to propyl. (2) The vinyl group cannot survive Friedel–Crafts or halogenation conditions (the alkene would react), so it is built last from an acetyl group, which also goes in by Friedel–Crafts acylation para to propyl — a site that is simultaneously ortho to Cl, exactly where the target needs it.

1. Benzene + CH₃CH₂COCl/AlCl₃ → propiophenone.
2. Cl₂/FeCl₃: the acyl group is a meta-director → 3-chloropropiophenone.
3. Clemmensen reduction (Zn(Hg)/HCl) → 1-chloro-3-propylbenzene (Cl now meta to propyl).
4. CH₃COCl/AlCl₃: propyl (the stronger, activating o,p-director) and Cl (a weak, deactivating o,p-director) are meta to each other, so both point at the same three sites. The bulky acylium ion avoids the crowded site between them and prefers the position para to the stronger activator (propyl), which is ortho to Cl → 1-(2-chloro-4-propylphenyl)ethan-1-one as the major isomer (the isomer ortho to propyl/para to Cl is the by-product to separate).
5. NaBH₄, CH₃OH → the secondary benzylic alcohol, Ar–CH(OH)–CH₃.
6. Dehydration (KHSO₄ or H₂SO₄, heat; or POCl₃/pyridine) → the conjugated styrene, 2-chloro-1-ethenyl-4-propylbenzene.